The present invention relates to a novel benzopyran or thiobenzopyran derivative having anti-estrogenic activity. More specifically, the present invention relates to a novel benzopyran or thiobenzopyran derivative represented by the following formula (1): 
pharmaceutically acceptable salt or stereoisomer thereof, in which
X represents O or S,
R1 represents hydrogen, hydroxy, or xe2x80x94OR6(wherein R6 represents acyl or alkyl),
R2 represents phenyl which is optionally substituted by one or more substituents selected from a group consisting of hydroxy, lower alkyl, halogen, nitro, hydroxymethyl, carboxy, alkoxycarbonyl, xe2x80x94OR6(wherein R6 represents acyl or alkyl) and amino which is optionally substituted by one or two lower alkyl or represents 5- or 6-membered unsaturated heterocycle containing nitrogen, oxygen or sulfur as the hetero atom,
R3 represents hydrogen or lower alkyl, provided that R3 does not exist when 
xe2x80x83is a double bond(wherein 
xe2x80x83represents a single bond or a double bond),
R4 represents hydrogen or lower alkyl,
A represents hydrogen, hydroxyalkyl, carboxyalkyl, carboxyvinylphenyl; pyrrole substituted by carboxyvinylbenzyl; or represents a group selected from the following formulae (a) to (l); 
xe2x80x83in the above formulae (a) to (l)
m1 to m3 independently of one another represent an integer of 0 to 15,
n1 to n2 independently of one another represent an integer of 0, 1 or 2,
R5 represents cyano, alkyl; halogenoalkyl; alkoxy; hydroxy; carboxy; alkoxycarbonyl; carbamoyl; monoalkylamino; phenyl which is optionally substituted by one or more substituents selected from a group consisting of straight-chain or branched alkyl, carboxy and cyano; piperidinyl which is optionally substituted by one or more substituents selected from a group consisting of carboxy, alkyl and alkoxycarbonyl; cyclohexyl which is optionally substituted by carboxy; imidazolyl; dialkylamino; or piperidinyl oxide,
D1 and D2 independently of one another represent a direct bond, or a group selected from the following: 
wherein
m, m1 and m2 independently of one another represent an integer of 0 to 15, and
R5 is defined as previously described,
and to a process for preparation thereof and a pharmaceutical composition having anti-estrogenic activity which contains the compound (1) as an active component.
In treating diseases caused by the abnormal tissue growth depending on a certain sexual steroidal hormone such as estrogen, it is very important to significantly inhibit, if possible, to completely remove the effect induced by said sexual steroidal hormone. For this purpose, it is desirable to block the receptor site which can be stimulated by sexual steroidal hormone and further, to reduce the level of sexual steroidal hormone capable of acting on said receptor site. For instance, as a substitution or combined therapy, administration of anti-estrogenic agents to limit the production of estrogen to the amount less than required to activate the receptor site may be used. However, prior methods for blocking the estrogen production could not sufficiently inhibit the effect induced through estrogen receptor. Practically, even when estrogen is completely absent, some of the receptors may be activated. Accordingly, it was considered that antagonists for estrogen can provide better therapeutic effect in comparison to the method for blocking only the production of sexual steroidal hormone. Thus, numerous anti-estrogenic compounds have been developed. For example, many patent publications including U.S. Pat. Nos. 4,760,061, 4,732,912, 4,904,661, 5,395,842 and WO 96/22092, etc. disclose various anti-estrogenic compounds. However, prior antagonists have sometimes insufficient affinity to the receptors. In some cases, moreover, they can combine to the receptor but act themselves as agonists, and therefore, activate rather than block the receptor. For example, Tamoxifen has been most widely used as an anti-estrogenic agent. However, it has a disadvantage that it exhibits estrogenic activity in some organs (see, M. Harper and A. Walpole, J. Reprod. Fertil., 1967, 13, 101). Therefore, it is required to develop the anti-estrogenic compound which has substantially or completely no agonistic effect and can effectively block the estrogenic receptor.
In addition, it has been known that 7xcex1-substituted derivatives of estradiol, for example, 7xcex1-(CH2)10CONMeBu derivative, exhibit anti-estrogenic activity (see, EP Appl. 0138504, U.S. Pat. No. 4,659,516). Further, estradiol derivative having xe2x80x94(CH2)9SOC5H6F5 substituent has also been disclosed (see, Wakeling et al., Cancer Res., 1991, 51, 3867) as steroidal anti-estrogenic agent without agonistic effect.
Non-steroidal anti-estrogenic drug without agonistic effect has been first reported by Wakeling et al. in 1987 (see, A. Wakeling and J. Bowler, J. Endocrinol., 1987, 112, R7). Meanwhile, U.S. Pat. No. 4,904,661 (ICI, Great Britain) discloses a phenol derivative having anti-estrogenic activity. This phenol derivative generally has a tetrahydronaphthalene structure and includes, typically, the following compounds: 
As other non-steroidal anti-estrogenic compounds, WO 93/10741 discloses a benzopyran derivative having aminoethoxyphenyl substituent (Endorecherche), of which the typical compound is EM-343 having the following structure: 
Accordingly, the present inventors have researched the anti-estrogenic activity of compounds having, various structures. As a result, we have identified that the benzopyran or thiobenzopyran derivatives represented by formula: (1), as defined above, can exhibit a good anti-estrogenic activity without agonistic activity, to be expected no undesirable side effect and thus, completed the present invention.
Therefore, the present invention relates to a novel benzopyran or thiobenzopyran derivative represented by the following formula (1): 
pharmaceutically acceptable salt or stereoisomer thereof, in which
X represents O or S,
R1 represents hydrogen, hydroxy, or xe2x80x94OR6(wherein R6 represents acyl or alkyl),
R2 represents phenyl which is optionally substituted by one or more substituents selected from a group consisting of hydroxy, lower alkyl, halogen, nitro, hydroxymethyl, carboxy, alkoxycarbonyl, xe2x80x94OR6(wherein R6 represents acyl or alkyl) and amino which is optionally substituted by one or two lower alkyl; or represents 5- or 6-membered unsaturated heterocycle containing nitrogen, oxygen or sulfur as the hetero atom,
R3 represents hydrogen or lower alkyl, provided that R3 does not exist when 
xe2x80x83is a double bond(wherein 
xe2x80x83represents a single bond or a double bond),
R4 represents hydrogen or lower alkyl,
A represents hydrogen; hydroxyalkyl; carboxyalkyl; carboxyvinylphenyl; pyrrole substituted by carboxyvinylbenzyl; or represents a group selected from the following formulae (a) to (l); 
xe2x80x83in the above formulae (a) to (l)
m1 to m3 independently of one another represent an integer of 0 to 15,
n1 to n2 independently of one another represent an integer of 0, 1 or 2,
R5 represents cyano; alkyl; halogenoalkyl; alkoxy; hydroxy; carboxy; alkoxycarbonyl; carbamoyl; monoalkylamino; phenyl which is optionally substituted by one or more substituents selected from a group consisting of straight-chain or branched alkyl, carboxy and cyano; piperidinyl which is optionally substituted by one or more substituents selected from a group consisting of carboxy, alkyl and alkoxycarbonyl; cyclohexyl which is optionally substituted by carboxy; imidazolyl; dialkylamino; or piperidinyl oxide,
D1 and D2 independently of one another represent a direct bond, or a group selected from the following: 
xe2x80x83wherein
m, m1 and m2 independently of one another represent an integer of 0 to 15, and
R5 is defined as previously described.
In addition, the present invention also relates to processes for preparing the benzopyran or thiobenzopyran derivative of formula (1).
Further, the present invention relates to a pharmaceutical composition having anti-estrogenic activity, which contains the compound of formula (1) as an active component.
In the present specification, the term xe2x80x9clower alkylxe2x80x9d denotes straight-chain or branched saturated hydrocarbon radicals having 1 to 6, preferable 1 to 4, carbon aoms; the term xe2x80x9chalogenoalkylxe2x80x9d denotes straight-chain or branched saturated hydrocarbon radicals having halogen atoms such as fluorine, chlorine, bromine, etc., preferably fluorine atom; and the term xe2x80x9calkylxe2x80x9d denotes straight-chain or branched saturated hydrocarbon radicals having 1 to 12 carbon atoms including lower alkyl as defined above.
The compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt. Such salt includes a salt with pharmaceutically acceptable acids such as asparagic acid, gluconic acid, hydrochloric acid, p-toluenesulfonic acid or citric acid, etc., a salt with bases such as pyridine or ammonia, etc., and a salt with acids or bases which are generally known and conventionally used in the technical field to which the benzopyran or thiobenzopyran derivative pertains. These pharmaceutically acceptable salts can be prepared according to a conventional conversion method.
In the compound of formula (1) wherein the bond between 3- and 4-positions of benzopyran or thiobenzopyran ring is a single bond, the two carbon atoms of 3- and 4-positions of the ring can be asymmetric, and thus the compound of formula (1) can exist as a pure stereoisomer such as enantiomer of R or S, diastereomer, etc., or a mixture thereof including racemate. Therefore, the present invention also includes each of these stereoisomers and their mixtures.
Among the novel compound of formula (1) according to the present invention, the preferred compounds include those wherein
X represents O or S,
R1 represents hydroxy,
R2 represents phenyl which is optionally substituted by one or more substituents selected from a group consisting of hydroxy, lower alkyl and halogen; or represents 6-membered unsaturated heterocycle containing nitrogen as the hetero atom,
R3 represents lower alkyl, provided that R3 does not exist when 
xe2x80x83is a double bond,
R4 represents hydrogen,
A represents a group selected from the following formulae (a) to (e), (k) and (l); 
xe2x80x83in the above formulae (a) to (e), (k) and (1)
m1 to m3 independently of one another represent an integer of 0 to 15,
n1 to n2 independently of one another represent an integer of 0, 1 or 2,
R5 represents alkyl; halogenoalkyl; alkoxy; hydroxy; carboxy; phenyl which is optionally substituted by one or two straight-chain or branched alkyl; or dialkylamino,
D1 and D2 independently of one another represent a direct bond, or a group selected from the following: 
xe2x80x83wherein
m, and m2 independently of one another represent an integer of 0 to 15, and
R5 is defined as previously described.
As specific example of the compound of formula (1) according to the present invention, the following compounds can be mentioned.
7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{9-[4-(4,4,5,5,5-pentafluoropentyl)piperazinyl]nonyl}chroman;
(3RS,4RS)-7-hydroxy-4-[(11-imino-11-N-butylamino)undecyl]-3-(4-hydroxyphenyl)-3-methylchroman;
(3RS,4RS)-7-hydroxy-4-[(11-N-butylimino-11-N-butylamino)undecyl]-3-(4-hydroxyphenyl)-3-methylchroman;
(3RS,4SR)-7-hydroxy-4-{4-{2-{4-{[3,5-bis(t-butyl)phenyl]methyl}piperazinyl}ethoxy }phenyl}-3-(4-hydroxyphenyl)-3-methylchroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)-propylamino]pentyl}-3-methylchroman;
4-{4-{2-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy]ethoxy}phenyl}-7-hydroxy-3-(4-hydroxyphenyl)-2H-chromene;
(3RS,4RS)-4-[9-(3-dimethylaminopropylsulfinyl)nonyl]-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman;
(3RS,4RS)-4-[9-(N-4,4,5,5,5-pentafluoropentylaminosulfonylamino)nonyl]-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman;
6-{(3RS,4RS)-{9-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]nonylsulfinyl}hexanoic acid;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{9-[2-(2-methoxyethoxy)ethylsulfinyl]nonyl}thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{9-[2-(2-hydroxyethoxy)ethylsulfinyl]nonyl}thiochroman;
(3RS,4RS)-7-hydroxy-3-(2-methylphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentyl)sulfinylnonyl]thiochroman;
(3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-3-(4-pyridyl)chroman,
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]thiochroman;
(3RS,4RS)-3-(4-fluorophenyl)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman;
(3RS,4RS)-3-(3-fluorophenyl)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-[N-5-(4,4,5,5,5-pentafluoropentylsulfinyl)pentylamino]propyl}chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(N-methyl-N-4,4,5,5,5-pentafluoropentyl)aminononyl]chroman;
N-methyl-N-(4,4,5,5,5-pentafluoropentyl)-9-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]nonylamine N-oxide;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy]phenoxy}propyl}thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[4-oxa-9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylaminosulfonyl)nonyl]chroman;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-{8-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]octyl}-(4,4,5,5,5-pentafluoropentyl)methane-1,1-dicarboxylic acid;
methyl-(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoate;
(3xe2x80x2RS,4xe2x80x2RS)-2-{8-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]octyl}-2-(4,4,5,5,5-pentafluoropentyl)propane-1,3-diol;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(9-(2-aza-2-carbonyl-1-(4,4,5,5,5-pentafluoropentylamino)ethenyl)aminononyl)thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(9-((1-((4,4,5,5,5-pentafluoropentyl)amino)-2-nitroethenyl)amino)nonyl)thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylsulfonylamino)octyl]chroman;
(3RS,4RS)-7-hydroxy-3-(4-(hydroxyphenyl)-3-methyl-4-[4-(4-piperidyl-butyloxy)phenyl]chroman;
(3RS,4RS)-7-hydroxy-3-methyl-3-(4-hydroxyphenyl)-4-(4-(3-(2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy)-(R)-2-hydroxypropyloxy)phenyl)chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{[4-(4,4,5,5,5-pentafluoropentylsulfinyl)butyloxy]butyl}chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{5-{N-methyl-N-[3-(4,4,5,5,5-pentafluoropentyl)sulfiny]propyl}aminopentyl}chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{5-{N-methyl-N-oxo-N-[3-(4,4,5,5,5-pentafluoropentyl)sulfinyl]propyl}aminopentyl}chroman;
(3xe2x80x2RS,4xe2x80x2RS)-2-(4-(7-hydroxy)-3-(4-hydroxyphenyl)-3-methylchroman-4-yl)butyl-6-(4-(4,4,5,5,5-pentafluoropentyl)sulfinyl)hexanoic acid;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(N-cyano-N-pentylcarbonyl)aminononyl]thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-(hydroxyphenyl)-3-methyl-4-[5-oxa-9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]chroman;
(3xe2x80x2RS,4xe2x80x2RS)-6,6,7,7,7-pentafluoro-2-(2-(4-(4-(7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl)butyl)phenyloxy)ethyl)heptanoic acid;
(3RS,4RS)-4-allyl-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{9-[2-(2,2,2-trifluoroethoxy)ethylsulfinyl]nonyl}thiochroman;
(3xe2x80x2RS,4xe2x80x2RS)-8-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]octanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-6-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]hexanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-7-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]heptanoic acid;
(3RS,4RS)-4-[4,7-dioxa-9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[6-oxa-9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[7-oxa-9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[5-oxa-9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]thiochroman;
(3xe2x80x2RS,4xe2x80x2RS)-9-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]nonanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]decanoic acid;
(E)-3-[7-hydroxy-3-(4-hydoxyphenyl)-2H-chromen-4-yl]phenylacrylic acid;
(3xe2x80x2RS,4xe2x80x2RS)-(E)-3-[7-hydroxy-3-(4-hydoxyphenyl)thiochroman-4-yl]phenyl acrylic acid;
(3RS,4RS)-4-[9-(4-cyanobutylsulfinyl)nonyl]-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman;
(3xe2x80x2RS,4xe2x80x2RS)-4-{7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman-3-yl}benzoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-4-{7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman-3-yl}benzyl alcohol;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-[3-(4,4,5,5,5fluoropentylsulfinyl)propylphenoxy]-1-propyl}chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-[3-(4,4,5,5,5-pentafluoropentylsulfonyl)propylphenoxy]-1-propyl}chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{4-[4-(4,4,5,5,5-pentafluoropentylsulfinylethyloxy)phenyl]-1-butyl}chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{4-[4-(4,4,5,5,5-pentafluoropentylsulfonyl-ethyloxy)phenyl-1-butyl}chroman;
(3xe2x80x2RS,4xe2x80x2RS)-1-[7-hydroxy-4-(4-hydroxyphenyl)-3-methylchroman-4-yl]-14,14,15,15,15-pentafluoropentadecan-10-ol;
(3RS,4RS)-7-hydroxy-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-3-(3-pyridyl)chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]chroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-(9-oxo-14,14,15,15,15-pentafluoro)pentadecyl-3-methylchroman;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-(9-hydroxy-10-hydroxycarbonyl-14,14,15,15,15-pentafluoro)pentadecyl-3-methylchroman;
(3RS,4RS)-7-hydroxy-4-[(10-ethoxycarbonyl-14,14,15,15,15-pentafluoro)pentadec-9-enyl]-3-(4-hydroxyphenyl)-3-methylchroman;
1,1,1,2,2-pentafluoro-14-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-5-pentadecanone;
(E)-6,6,7,7,7-pentafluoro-2-{9-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]nonyl}-2-heptenoic acid;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylsulfonylamino)nonyl]chroman;
(3RS,4RS)-(E)-3-{4-[7-hydroxy-3-(4-hydroxyphenyl)thiochromen-4-yl]phenyl}propenoic acid;
(3RS,4RS)-(E)-3-{4-[7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]phenyl}propenoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-(E)-3-{4-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]phenyl}propenoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-N-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)]ethyl-4-{4-[7-hydroxy-3-(4-hydryoxyphenyl)-3-methylchroman-4-yl]butyl}phenyl-N-methylamin;
6-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)hexanoic acid;
7-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)heptanoic acid;
8-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)octanoic acid;
9-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
(3RS,4RS)-9-(7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
(3RS,4RS)-9-(7-hydroxy-3-(4-hydroxyphenyl)-3-thiochroman-4-yl-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-4-{[11-carboxyl-11-(4,4,5,5,5-pentafluoropentyl)]undecyl}-3-methylthiochroman;
(3RS,4RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
9-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
8-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)octanoic acid;
7-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)heptanoic acid;
6-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)hexanoic acid;
5-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)pentanoic acid;
5-{4-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]phenoxy}-2-(4,4,5,5,5-pentafluoropentyl)pentanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-12-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-12-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)dodecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-9-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-9-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,4-pentafluorobutyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,4-pentafluorobutyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(3,3,4,4,4-pentafluorobutyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(3,3,4,4,4-pentafluorobutyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-methyl-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-methyl 2-(4,4 5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-ethyl-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-ethyl-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(4,4,5,5,5-pentafluoropentyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-methyl-2-(5 5,6,6,6-pentafluorohexyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-methyl-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-ethyl-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-11-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-ethyl-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-methyl-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-methyl-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-methyl-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-ethyl-2-(5,5,6,6,6-pentafluorohexyl)decanoic acid;
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylchroman-4-yl]-2-ethyl-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid; or
(3xe2x80x2RS,4xe2x80x2RS)-10-[7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-ethyl-2-(6,6,7,7,7-pentafluoroheptyl)decanoic acid.
The present invention also provides the following processes I to V for preparing the compound of formula (1) as defined above.
[Process I]
First, the compound of formula (1) wherein A represents hydrogen, that is a compound of formula (2): 
wherein X, R1, R2, R3 and R4 are defined as previously described, can be prepared by the reduction of the ketone of formula (3): 
wherein X, R3 and R4 are defined as previously described, and P represents a hydroxy-protecting group.
In the following processes for preparing the compound of formula (1) according to the present invention including the process for preparing the compound of formula (1) wherein A represents hydrogen, suitable hydroxy-protecting groups and leaving groups which have been conventionally used in the technical field to which the present invention pertains or which can be easily selected by a person skilled in the art may be used. Preferably, methoxymethyl or t-butyldimethylsilyl as the hydroxy-protecting group and tosyloxy, mesyloxy, halo or acetyl as the leaving group can be mentioned.
Further, if not specifically mentioned, any organic solvents which do not adversely affect the reaction can be used as the solvent in the processes according to the present invention. These solvents may be used under anhydrous condition if such a condition is required due to the nature of the reaction. Only the solvents particularly appropriate are mentioned for the respective reaction steps in the present specification. The reactions may be carried out under cooling to warming or heating, and the reaction temperature and time are organically combined together to contribute to the reaction completion.
[Process II]
The compound of formula (1) wherein A represents hydroxyalkyl, that is a compound of formula (4): 
wherein X, R1, R2, R3, R4 and m1 are defined as previously described, can be prepared using the same procedure described in International Patent Appln. No. PCT/KR97/00265.
[Process III]
The compound of formula (1) wherein A represents carboxyalkyl, that is a compound of formula (5): 
wherein X, R1, R2, R3, R4 and m1 are defined as previously described, can be prepared by a process characterized in that
(a) the compound of formula (6): 
xe2x80x83wherein X, R3, R4, m1 and P are defined as previously described, is oxidized and deprotected to produce a compound of formula (5a): 
xe2x80x83wherein X, R3, R4 and m1 are defined as previously described, or
(b) the compound of formula (7): 
xe2x80x83wherein X, R3, R4, m2 and P are defined as previously described, is reacted with a Wittig reagent and the resulting compound is hydrogenated and deprotected to produce a compound of formula (5a): 
xe2x80x83wherein X, R3, R4 and m1 are defined as previously described.
[Process IV]
The compound of formula (1) wherein A represents carboxyvinylphenyl, that is a compound of formula (8): 
wherein X, R1, R2, R3 and R4 are defined as previously described, can be prepared by a process characterized in that a compound of formula (9): 
wherein X, R3, R4 and P are defined as previously described, is reacted with a compound of formula (10): 
wherein L represents acetal or nitrile or protected-hydroxymethyl group, and the resulting compound is deprotected or hydrogenated or dehydrated or oxidized to produce a compound of formula (11): 
wherein X, R3, R4 and P are defined as previously described, and the resulting compound of formula(11) is reacted with malonic acid derivative and is deprotected to produce a compound of formula (12): 
wherein X, R3 and R4 are defined as previously described.
[Process V]
(Method A)
The compound of formula (1) wherein A represents group (a), that is a compound of formula (1a). 
wherein X, R1, R2, R3, R4, R5, m1, m2 and D1 are defined as previously described, can be prepared by a process characterized in that
(a) a compound of formula (13) 
xe2x80x83wherein X, R3, R4, m1 and P are defined as previously described, and W1 represents a leaving group, is reacted with a compound of formula (14):
D1H2xe2x80x83xe2x80x83(14)
xe2x80x83wherein D1 is defined as previously described, to produce a compound of formula (15): 
xe2x80x83wherein X, R3, R4, D1, m1 and P are defined as previously described, the resulting compound of formula (15) is reacted with a compound of formula (16):
W2xe2x80x94(CH2)m2xe2x80x94R5xe2x80x83xe2x80x83(16)
xe2x80x83wherein R5 and m2 are defined as previously described, and W2 represents a leaving group such as acyl, hydrogen, etc., and then deprotected to produce a compound of formula (1aa): 
xe2x80x83wherein X, R3, R4, R5, m1, m2 and D1 are defined as previously described, or
(b) the compound of formula (13) is reacted with sodium cyanide to produce a compound of formula (17): 
xe2x80x83wherein X, R3, R4, m1 and P are defined as previously described the resulting compound of formula (17) is reacted with a compound of formula (18):
H2Nxe2x80x94(CH2)m2xe2x80x94R5xe2x80x83xe2x80x83(18)
xe2x80x83wherein R5 and m2 are defined as previously described, in the presence of a Lewis acid to produce a compound of formula (1ab) or (1ac): 
xe2x80x83wherein X, R3, R4, R5, m1 and m2 are defined as previously described.
In the method A(a) for preparing the compound of formula (1a), the coupling step of the compound (13) and (14) may be carried out in a solvent. As the preferable solvent, one or more selected from a group consisting of dioxane, methanol, ethanol, diethylether, tetrahydrofuran, dimethylsulfoxide, methylene chloride, dimethylformamide, chloroform, ethyl acetate, acetonitrile and acetone can be used. This reaction may be carried out optionally in the presence of one or more inorganic or organic bases selected from a group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, triethylamine and cesium carbonate. The reaction may be suitably proceeded under the reflux temperature of the solvent used or room temperature, if appropriate, under ice-cooling.
The compound of formula (15) resulted from the coupling of compounds (13) and (14) is reacted with the compound of formula (16) and then deprotected to produce the compound of formula (1aa). This reaction can be carried out in one or more solvents selected from a group consisting of acetone, toluene, dimethylformamide, acetonitrile, dimethylsulfoxide and methylene chloride, optionally in the presence of a base such as potassium carbonate, triethylamine, sodium ethoxide, etc. The deprotection reaction may be carried out according to a conventional method such as hydrolysis in the presence of acid or base, and reduction, etc. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid, hydrofluoric acid, pyridinium-p-toluenesulfonate and sulfuric acid, or in the presence of one or more reducing agents selected from a group consisting of Pd(OH)2/C under hydrogen, Pd/C and diisobutylaluminum hydride(DIBAL). This reaction can be carried out under a low temperature to warming, preferably carried out by starting at a low temperature of xe2x88x9278xc2x0 C. and then warming to room temperature. While, the compound of formula (1aa) thus produced may be further oxidized using metachloroperbenzoic acid(mCPBA) in a solvent such as chloroform.
In the method A(b), the compound of formula (13) is first reacted with sodium cyanide to produce the compound of formula (17). In this reaction, one or more solvents selected from dimethylsulfoxide, acetonitrile and dimethylformamide can be used. The compound (17) thus produced is reacted with the compound of formula (18) in the presence of a Lewis acid to give the compound of formula (1ab) or (1ac). As the Lewis acid which can be used, AlCl3, BF3.Et2O, SnCl4, Znl2 or FeCl3 can be mentioned, and as the solvent one or more selected from xylene, benzene and toluene can be mentioned. Preferably, the reaction is proceeded at the reflux temperature of the solvent used for 1 to 20 hours.
(Method A-1)
The compound of formula (1a) wherein R1, R2, R3, R4 and D1 represent xe2x80x94OH, xe2x80x94C6H4(OH), xe2x80x94Me, H and (xe2x80x94CH(CO2H)xe2x80x94) respectively may typically be synthesized by the following methods. 
wherein X, R5, m1 and m2 are defined as previously described; A10 and A11 are protecting group such as t-butyldimethylsilyl, triisopropylsilyl, triethylsilyl, t-buthydiphenylmethylsilyl, methoxymethyl, tertahydropyranyl, methyl, etc.; L10 is a leaving group such as methansulfonyl, p-toluenesulfonyl, etc.; M is a methal such as Li, Na, K, etc.; Y10 is a halogen such as Cl, Br, I, etc., R20 is alkyl group such as methyl, ethyl, etc.; and m10 is an integer of 0 to 12.
The compound (12aa) may be synthesized in the following manner.
The compund represented by the formula (26aa) is reacted with acetylene (13aa) in the presence of base such as n-buthyllithium, sec-buthyllithium, sodium hydride, in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, chloroform, preferably in tetrahydrfuran or dioxane, at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture, preferably at xe2x88x9278xc2x0 C. through room temperature, to yield the compound represented by the formula (2aa).
The compound represented by the formula (2aa) is reduced by sodium cyanoborohydride in the presence of Lewis acid such as zinc iodide, in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in dichloroethane at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture, preferably at 0xc2x0 C. through room temperature, to yield the compound represented by the formula (3aa).
The compound represented by the formula (3aa) is hydrogenated with a catalyst such as palladium on activated carbon, palladium hydroxide, platinum oxide, in a solvent inert to the reaction such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform, preferably in tetrahydrofuran, ethyl acetate at the temperature between room temperature and the boiling point of the reaction mixture, preferably, at room temperature, optionally in the presence of sodium hydrogen carbonate, to yield the compound represented by the formula (4aa). The compound represented by the formula (4aa) is also obtained from the compound represented by the formula (2aa) directly by hydrogenation reaction with a catalyst such as palladium on activated carbon, palladium hydroxide or platinum oxide, in a solvent inert to the reaction such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, ethyl acetate at the temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature.
The compound represented by the formula (4aa) is treated with tetrabuthylammonium fluoride or cesium fluoride or hydrogen fluoride-pyridine in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, at the temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature to yield the compound represented by the formula (5aa).
The compound represented by the formula (5aa) is treated with methanesulfonyl chloride or p-toluenesulfonylchloride in the presence of an organic base such as triethylamine or pyridine in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in dichloromethane, at the temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature to yield the compound represented by the formula (6aa).
The compound represented by the formula (6aa) is treated with metalhalide such as sodium iodide or potassium iodide in a solvent inert to the reaction such as acetone, tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in dichloromethane, at the temperature between room temperature and the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture, to yield the compound represented by the formula (7aa).
The compound represented by the formula (7aa) is reacted with malonate such as diethyl malonate or dimethyl malonate in the presence of a base such as sodium hydride, sodium hydroxide or potassium t-butoxide, in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, at the temperature between room temperature and the boiling point of the reaction mixture to yield the compound represented by the formula (8aa). The compound represented by the formula (8aa) is also obtained from the compound represented by the formula (6aa) directly by the reaction with malonate such as diethyl malonate or dimethyl malonate in the presence of a base such as sodium hydride, sodium hydroxide or potassium t-butoxide, in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, at the temperature between room temperature and the boiling point of the reaction mixture.
The compound represented by the formula (8aa) is reacted with alkylhalide as the compound represented by the formula (14aa) in the presence of a base such as sodium hydride, sodium hydroxide or potassium t-butoxide in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, at the temperature between room temperature and the boiling point of the reaction mixture to yield the compound represented by the formula (9aa).
The compound represented by the formula (9aa) is treated with sodium hydroxide or potassium hydroxide in a solvent such as water, ethanol, methanol, a mixture of water-ethanol or a mixture of water-methanol at the temperature between room temperature and the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture to yield the compound represented by the formula (10aa).
The compound represented by the formula (10aa) is heated at 50xc2x0 C. to the boiling point of the reaction mixture in a solvent such as dimethylsulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran, optionally in the presence of an acid such as hydrogen chloride, sulfuric acid or p-toluenesulfonic acid, to yield the compound represented by the formula (11aa).
The compound represented by the formula (11aa) is treated with an acid, such as hydrogen chloride, sulfuric acid, hydrogen bromide, hydrogen pyridinium chloride, boron tribromide at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture to yield the compound represented by the formula (12aa). 
wherein X, R5, m1, m2 and A11 are defined as previously described.
The compound (12aa) may be synthesized in the following manner.
The compound represented by the formula (10aa) is treated with an acid, such as hydrogen chloride, sulfuric acid, hydrogen bromide, hydrogen pyridinium chloride or boron tribromide at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture to yield the compound represented by the formula (16aa).
The compound represented by the formula (16aa) is heated at 50xc2x0 C. to the boiling point of the reaction mixture in a solvent such as dimethylsulfoxide, dimethylformamide, benzene, toluene, xylene, dioxane or tetrahydrofuran, optionally in the presence of an acid such as hydrogen chloride, sulfuric acid or p-toluenesulfonic acid, to yield the compound represented by the formula (12aa). 
wherein X, R5, R20, Y10, A11, m1 and m2 are defined as previously described.
The compound represented by the formula (25aa) is reacted with malonate such as diethyl malonate or dimethyl malonate in the presence of a base such as sodium hydride, sodium hydroxide or potassium t-butoxide, in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture to yield the compound represented by the formula (15aa).
The compound represented by the formula (15aa) is reacted with the compound represented by the formula (7aa) in the presence of a base such as sodium hydride, sodium hydroxide or potassium t-butoxide in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in tetrahydrofuran, at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture to yield the compound represented by the formula (9aa).
The compound represented by the formula (9aa) is converted to the compound represented by the formula (12aa) according to the previously described method. 
wherein X, R5, R20, A11, m1 and m2 are defined as previously described; m11 and m12 are an integer of 0 to 10.
The compound (12aa) may be synthesized in the following manner.
The compound represented by the formula (17aa) is reacted with the compound represented by the formula (18aa) in the presence of a catalyst such as benzylidene-bis(tricyclohexylphosphine)dichlororuthenium in a solvent such as methylene chloride, chloroform, benzene, toluene, xylene, dioxane, tetrahydrofuran, dimethylsulfoxide or dimethylformamide at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture to, preferably at the boiling point of the reaction mixture, yield the compound represented by the formula (19aa)
The compound represented by the formula (19aa) is hydrogenated with a catalyst such as palladium on activated carbon, palladium hydroxide, platinum oxide or Wilkinson""s catalyst in a solvent inert to the reaction such as methanol, ethanol, ethyl acetate, tetrahydrofuran, dioxane, dichloromethane, dichloroethane, chloroform or benzene at the temperature between room temperature and the boiling point of the reaction mixture, preferably at room temperature to yield the compound represented by the formula (20aa).
The compound represented by the formula (20aa) is treated with sodium hydroxide or potassium hydroxide in a solvent such as water, ethanol, methanol, a mixture of water-ethanol or a mixture of water-methanol at the temperature between room temperature and the boiling point of the reaction mixture, preferably at the boiling point of the reaction mixture to yield the compound represented by the formula (11aa).
The compound represented by the formula (11aa) is converted to the compound represented by the formula (12aa) according to the previously described method.
(Method A-2)
The compound of formula (17aa) may typically be synthesized by the following methods. 
wherein X, A11, m11 and Y10 are defined as previously described.
The compound (17aa) may be synthesized in the following manner.
The compound represented by the formula (21aa) is reacted with the Grignard reagent represented by the formula (23aa) in a solvent inert to the reaction such as diethyl ether, benzene, toluene, xylene, dioxane or tetrahydrofuran at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture, to yield the compound represented by the formula (22aa).
The compund represented by the formula (22aa) is reduced by sodium cyanoborohydride in the presence of Lewis acid such as zinc iodide, or by triethylsilane in the presence of an acid such as trifluoroacetic acid, in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane or chloroform, preferably in dichloroethane at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture, preferably at 0xc2x0 C. through room temperature, to yield the compound represented by the formula (17aa). 
wherein X, A11 and m11 are defined as previously described.
The compound (17aa) may be synthesized in the following manner.
The compound represented by the formula (21aa) is reduced by a reagent such as sodium borohydride or lithium aluminum hydride in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane, or chloroform at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture, preferably at the temperature between 0xc2x0 C. and room temperature, to yield the compound represented by the formula (24aa).
The compound represented by the formula (24aa) is reacted with the compound represented by the formula (25aa) in the presence of a Lewis acid such as zinc iodide or boron trifluoride diethyl etherate in a solvent inert to the reaction such as tetrahydrofuran, dioxane, dichloromethane, dichloroethane, or chloroform at the temperature between xe2x88x9278xc2x0 C. and the boiling point of the reaction mixture to yield the compound represented by the formula (17aa).
The above compound (17aa) is novel.
(Method B)
The compound of formula (1) wherein A represents group (b), that is a compound of formula (1b): 
wherein X, R1, R2, R3, R4, R5, m1, m2 and D1 are defined as previously described, can be prepared by a process characterized in that a compound of formula (19): 
wherein X, R3, R4, m1, W1 and P are defined as previously described, is reacted with a compound of formula (20):
HD1xe2x80x94(CH2)m2xe2x80x94R5xe2x80x83xe2x80x83(20)
wherein R5, m2 and D1 are defined as previously described, and then deprotected to produce a compound of formula (1ba): 
wherein X, R3, R4, R5, m1, m2 and D1 are defined as previously described.
The reaction of the compound (19) with (20) is preferably carried out in one or more solvents selected from acetone, dimethylformamide, methylene chloride and chloroform at the reflux temperature of the solvent used. In addition, a base such as potassium carbonate, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, tetra-n-butylammonium bromide, etc. may be used to more facilitate the reaction.
(Method C)
The compound of formula (1) wherein A represents group (c), that is a compound of formula (1c): 
wherein X, R1, R2, R3, R4, R5, m1, m2, m3, n1 and D1 are defined as previously described, can be prepared by a process characterized in that a compound of formula (21): 
wherein X, R4, m1, m2, D1, W1 and P are defined as previously described, is reacted with a compound of formula (22):
W2xe2x80x94Sxe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(22)
wherein R5, m3 and W2 are defined as previously described, to produce a compound of formula (23): 
wherein X, R4, R5, m1, m2, m3, D1 and P are defined as previously described, the resulting compound of formula (23) is deprotected and dehydrated to produce a compound of formula (24): 
wherein X, R4, R5, m1, m2, m3 and D1 are defined as previously described, which is then oxidized to produce a compound of formula (1ca): 
wherein X, R4, R5, m1, m2, m3 and D1 are defined as previously described, and n1xe2x80x2 represents 1 or 2.
The compound of formula (21) is reacted with the compound of formula (22) in one or more solvents selected from methanol, ethanol and acetonitrile and optionally in the presence of one or more bases selected from sodium hydroxide, sodium ethoxide and sodium methoxide under warming for 1 to 20 hours to produce the coupling product of formula (23). Deprotection and dehydration reactions are subjected to the resulting compound of formula (23) to prepare the compound of formula (24). The deprotection and dehydration reaction may be carried out by applying the reaction conditions which are generally used for this purpose. This reaction is preferably carried out by refluxing under argon in the presence of a salt such as pyridinium p-toluenesulfonate.
The desired compound of formula (1ca) is produced by oxidizing the compound of formula (24). The oxidation reaction can be carried out under the condition selected from the various possible conditions based on the structure and nature of the compound to be oxidized. Generally, the oxidation is carried out in one or more solvents selected from methanol, water, chloroform, tetrahydrofuran, dioxane, ethanol and methylene chloride in the presence of one or more oxidizing agents selected from sodium periodate(NaIO4), metachloroperbenzoic acid, hydrogen peroxide and OxoneR(monopersulfate compound; DuPont product). Hereinafter, the oxidation reactions for the other compounds having different structures can be explained in the same manner.
(Method D)
The compound of formula (1) wherein A represents group (d), that is a compound of formula (1d): 
wherein X, R1, R2, R3, R4, R5, m1, m2, m3, n1, D1 and D2 are defined as previously described, can be prepared by a process characterized in that
(a) the compound of formula (13): 
xe2x80x83wherein X, R3, R4, m1, P and W1 are defined as previously described, is reacted with a compound of formula (25):
HD1xe2x80x94(CH2)m2xe2x80x94S(O)n1xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(25)
xe2x80x83wherein R5, m2, m3, n1 and D1 are defined as previously described, and then deprotected to produce a compound of formula (1da): 
xe2x80x83wherein X, R3, R4, R5, m1, m2, m3, n1 and D1 are defined as previously described,
(b) the compound of formula (15): 
xe2x80x83wherein X, R3, R4, D1, m1 and P are defined as previously described, is reacted with a compound of formula (26): 
xe2x80x83wherein n1 and W2 are defined as previously described, Pxe2x80x2 represents a hydroxy-protecting group, and D2xe2x80x2 is the same with D2, provided that 1 or 2 hydrogen atoms are excluded therefrom, to produce a compound of formula (27): 
xe2x80x83wherein X, R3, R4, m1, n1, D1, D2xe2x80x2, P and Pxe2x80x2 are defined as previously described, the resulting compound of formula (27) is condensed with a compound of formula (28):
HOxe2x80x94(CH2)m2xe2x80x94R5xe2x80x83xe2x80x83(28)
xe2x80x83wherein R5 and m2 are defined as previously described, and then deprotected to produce a compound of formula (1db): 
xe2x80x83wherein X, R3, R4, R5, m1, m2, n1, D1 and D2 are defined as previously described,
(c) the compound of formula (13) is reacted with a compound of formula (29):
W2xe2x80x94Sxe2x80x94D2xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(29)
xe2x80x83wherein R5, m3, D2 and W2 are defined as previously described, to produce a compound of formula (30): 
xe2x80x83wherein X, R3, R4, R5, m1, m3, D2 and P are defined as previously described, the resulting compound of formula (30) is then deprotected and oxidized to produce a compound of formula (1dc): 
xe2x80x83wherein X, R3, R4, R5, m1, m3, n1xe2x80x2 and D2 are defined as previously described,
(d) the compound of formula (13) is reacted with a compound of formula (29a):
W2xe2x80x94Sxe2x80x94D2xe2x80x94(CH2)m3xe2x80x94R5xe2x80x2xe2x80x94Pxe2x80x2xe2x80x83xe2x80x83(29a)
xe2x80x83wherein m3, D2, Pxe2x80x2 and W2 are defined as previously described, and R5xe2x80x2 is the same with R5, provided that 1 or 2 hydrogen atoms are excluded therefrom, to produce a compound of formula (30a): 
xe2x80x83wherein X, R3, R4, R5xe2x80x2, m1, m3, D2, P and Pxe2x80x2 are defined as previously described, the resulting compound of formula (30a) is then deprotected and oxidized to produce the compound of formula (1dc),
(e) the compound of formula (13) is reacted with sodium azide and then reduced to produce a compound of formula (31): 
xe2x80x83wherein X, R3, R4, m1 and P are defined as previously described, the resulting compound of formula (31) is reacted with a compound of formula (32):
W2xe2x80x94SO2xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(32)
xe2x80x83wherein R5, m3 and W2 are defined as previously described, and then deprotected to produce a compound of formula (1dd): 
xe2x80x83wherein X, R3, R4, R5, m1 and m3 are defined as previously described,
(f) the compound of formula (31) is reacted with a compound of formula (32a):
OHC(CH2)m2xe2x80x2xe2x80x94S(O)n1xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(32a)
xe2x80x83wherein R5, m3, and n1 are defined as previously described, and m2xe2x80x2 equals m2xe2x88x921, and then deprotected to produce a compound of formula (1de): 
xe2x80x83wherein X, R3, R4, R5, m1, m2, m3 and n1 are defined as previously described,
(g) a compound of formula (33): 
xe2x80x83wherein X, R3, R4, m1, m2, D1, W1 and P are defined as previously described, is reacted with the compound of formula (22):
W2xe2x80x94Sxe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(22)
xe2x80x83wherein R5, m3 and W2 are defined as previously described, to produce a compound of formula (34): 
xe2x80x83wherein X, R3, R4, R5, m1, m2, m3, D1 and P are defined as previously described, the resulting compound of formula (34) is then deprotected and oxidized to produce a compound of formula (1df): 
xe2x80x83wherein X, R3, R4, R5, m1, m2, m3 and D1 are defined as previously described, or
(h) a compound of formula (35): 
xe2x80x83wherein X, R3, R4, m1, n1, W1 and P are defined as previously described, is reacted with a compound of formula (36):
Pxe2x80x2xe2x80x94D2xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(36)
xe2x80x83wherein R5, m3, D2 and Pxe2x80x2 are defined as previously described, and then deprotected to produce a compound of formula (1dg): 
xe2x80x83wherein X, R3, R4, R5, m1, m3, n1 and D2 are defined as previously described.
The above methods D(a) to D(h) will be explained more in detail in due order hereinafter.
In the method D(a), the compound of formula (13) is coupled with the compound of formula (25) and then deprotected to produce the compound of formula (1da). The reaction conditions explained for the preparation of the compound of formula (1aa) can be referred to in this coupling and deprotection reaction.
In the method D(b), the compound of formula (27) is prepared by reacting the compound of formula (15) with the compound of formula (26) in a solvent such as methylene chloride in the presence of one or more organic bases selected from triethylamine, pyridine, diisopropylamine and dimethylethylamine under a low temperature. The compound of formula (27) thus prepared is condensed with the compound of formula (28) and then deprotected to produce the desired compound of formula (1db). The condensation reaction may be carried out optionally in one or more solvents selected from methylene chloride, tetrahydrofuran, acetonitrile and dimethylformamide, and in the presence of a condensing agent such as triphenylphosphine, diethylazodicarboxylate, etc.
In the methods D(c) and D(d), the compound of formula (13) is coupled with the compound of formula (29) or (29a), respectively, to produce the compound of formula (30) or (30a), and the resulting compound (30) or (30a) is then deprotected and oxidized to produce the desired compound of formula (1dc). The optimum reaction condition for the structure of the compound to be reacted can be established by referring to the process for preparing the compound of formula (1aa) for the coupling and deprotection reaction, and referring to the process for preparing the compound of formula (1ca) for the oxidation reaction, respectively.
In the method D(e), the compound of formula (13) is first reacted with sodium azide, and then reduced to produce the amine compound of formula (31). The reaction with sodium azide is preferably carried out in one or more solvents selected from dimethylformamide, acetonitrile, methylene chloride, chloroform and tetrahydrofuran and optionally under nitrogen. The reduction is also carried out using a reducing agent such as Pd/C or Pd(OH)2/C under hydrogen in one or more solvents selected from methanol, ethanol, ethyl acetate and methylene chloride. The amine compound of formula (31) thus obtained is coupled with the compound of formula (32) and then deprotected to produce the desired compound of formula (1dd). The reaction conditions explained for the preparation of the compound of formula (1aa) can be referred to in this coupling and deprotection reaction.
In the method D(f) for preparing the compound of formula (1de), the compound of formula (31) prepared in the above method D(e) is used as the starting material. That is, the compound of formula (31) is coupled with the aldehyde compound of formula (32a) and then deprotected to produce the compound of formula (1de). Here, the coupling reaction with the aldehyde compound is preferably carried out in the presence of a reducing agent such as sodium cyanoborohydride in one or more solvents selected from methanol, methylene chloride, diethylether and dichloroethane. Also, the reaction conditions explained for the preparation of the compound of formula (1aa) can be referred to in this deprotection reaction.
In the method D(g), the compound of formula (33) is first coupled with the compound of formula (22) to produce the compound of formula (34), and the resulting compound (34) is subjected to deprotection and oxidation reaction to produce the desired compound of formula (1df). Here, the optimum reaction condition for the compound to be reacted can be established by referring to the process for preparing the compound of formula (1aa) for the coupling and deprotection reaction, and referring to the process for preparing the compound of formula (1ca) for the oxidation reaction, respectively.
In the method D(h), the compound of formula (35) is first coupled with the compound of formula (36) and then deprotected to produce the desired compound of formula (1dg). Here, the optimum reaction condition for the compound to be reacted can be established by referring to the process for preparing the compound of formula (1aa) for the coupling and deprotection reaction.
(Method E)
The compound of formula (1) wherein A represents group (e), that is a compound of formula (1e): 
wherein X, R1, R2, R3, R4, R5, m1, m2, m3, nand n2 are defined as previously described, can be prepared by a process characterized in that a compound of formula (13): 
wherein X, R3, R4, m1, P and W1 are defined as previously described, is reacted with a compound of formula (37):
W3Sxe2x80x94(CH2)m2xe2x80x94S(O)n2xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(37)
wherein R5, m2, m3 and n2 are defined as previously described and W3 represents acyl group, and the resulting compound is then deprotected and oxidized to produce a compound of formula (1ea): 
wherein X, R3, R4, R5, m1, m2, m3, n1 and n2 are defined as previously described.
The reaction of the compound (13) and (37) can be carried out in one or more solvents selected from methanol, ethanol and acetonitrile and optically in the presence of one or more bases selected from sodium hydroxide, sodium ethoxide and sodium methoxide under warming for 1 to 20 hours. The deprotection can be carried out using a conventional method such as hydrolysis in the presence of acid or base. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing, agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid and pyridinium-p-toluenesulfonate. The oxidation can be carried out under the condition selected from the various conditions based on the structure and nature of the compound. Generally, the oxidation is carried out in one or more solvents selected from methanol, water, chloroform, tetrahydrofuran, dioxane, ethanol and methylene chloride in the presence of one or more oxidizing agents selected from sodium periodate, metachloroperbenzoic acid, hydrogen peroxide and OxoneR(monopersulfate compound; DuPont product).
(Method F)
The compound of formula (1) wherein A represents group (f), that is a compound of formula (1f): 
wherein X, R1, R2, R3, R4, R5, m1, m2, n1 and n2 are defined as previously described, can be prepared by a process characterized in that a compound of formula (38): 
wherein X, R3, R4, m1, P and W1 are defined as previously described, is reacted with a compound of formula (39):
W3xe2x80x94S(O)n2xe2x80x94(CH2)m2R5xe2x80x83xe2x80x83(39)
wherein R5, m2 and W3 are defined as previously described, and the resulting compound is then deprotected and oxidized to produce a compound of formula (1fa); 
wherein X, R3, R4, R5, m1, m2, n1, and n2 are defined as previously described.
The reaction of the compound (38) and (39) can be carried out in one or more solvents selected from methanol, ethanol and acetonitrile and optically in the presence of one or more bases selected from sodium hydroxide, sodium ethoxide and sodium methoxide under warming for 1 to 20 hours. The deprotection can be carried out using a conventional method such as hydrolysis in the presence of acid or base. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a croup consisting of borontribromide, hydrochloric acid, hydrobromic acid and pyridinium-p-toluenesulfonate. The oxidation can be carried out under the condition selected from the various conditions based on the structure and nature of the compound. Generally, the oxidation is carried out in one or more solvents selected from methanol water, chloroform, tetrahydrofuran, dioxane, ethanol and methylene chloride in the presence of one or more oxidizing agents selected from sodium periodate, metachloroperbenzoic acid, hydrogen peroxide and OxoneR(monopersulfate compound; DuPont product).
(Method G)
The compound of formula (1) wherein A represents group (g), that is a compound of formula (1g): 
wherein X, R1, R2, R3, R4, R5, m1 and n1 are defined as previously described, can be prepared by a process characterized in that a compound of formula (38): 
wherein X, R3, R4, m1, P, and W1 are defined as previously described, is reacted with a compound of formula (40):
W4xe2x80x94R5xe2x80x83xe2x80x83(40)
wherein R5 is defined as previously described, W4 represents hydrogen, and the resulting compound is then deprotected to produce a compound of formula (1ga); 
wherein X, R3, R4, R5, m1 and n1 are defined as previously described.
The reaction of the compound (38) and (40) can be carried out in one or more solvents selected from methanol, ethanol and acetonitrile under refluxing for 1 to 48 hours. The deprotection can be carried out using a conventional method such as hydrolysis in the presence of acid or base. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid and pyridinium-p-toluenesulfonate.
(Method H)
The compound of formula (1) wherein A represents group (h), that is a compound of formula (1h): 
wherein X, R1, R2, R3, R4 and m1 are defined as previously described, can be prepared by a process characterized in that a compound of formula (41): 
wherein X, R3, R4, m1, P and W1 are defined as previously described, is reacted with a compound of formula (42): 
wherein W4 is defined as previously described, and the resulting compound is then deprotected to produce a compound of formula (1ha): 
wherein X, R3, R4 and m1 are defined as previously described.
The reaction of the compound (41) and (42) can be carried out in one or more solvents selected from methanol, ethanol and acetonitrile under refluxing for 1 to 48 hours. The deprotection can be carried out using a conventional method such as hydrolysis in the presence of acid or base. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid and pyridinium-p-toluenesulfonate.
(Method I)
The compound of formula (1) wherein A represents group (i), that is a compound of formula (1i): 
wherein X, R1, R2, R3, R4, R5, D1, D2, m1, m2, m3 and n1 are defined as previously described, can be prepared according to the similar procedure as Method D.
(Method J)
The compound of formula (1) wherein A represents group (j), that is a compound of formula (1j): 
wherein X, R1, R2, R3, R4, R5, m1 and n1 are defined as previously described, can be prepared by a process characterized in that a compound of formula (41): 
wherein X, R3, R4, m1, P and W1 are defined as previously described, is reacted with a compound of formula (43):
W3xe2x80x94S(O)n1xe2x80x94R5xe2x80x83xe2x80x83(43)
wherein R5, n1 and W3 are defined as previously described, and the resulting compound is then deprotected and oxidized to produce a compound of formula (1ja): 
wherein X, R3, R4, R5, m1 and n1 are defined as previously described.
The reaction of the compound (41) and (43) can be carried out in one or more solvents selected from methanol, ethanol and acetonitrile and optically in the presence of one or more bases selected from sodium hydroxide, sodium ethoxide and sodium methoxide under warming for 1 to 20 hours. The deprotection can be carried out using a conventional method such as hydrolysis in the presence of acid or base. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid and pyridinium-p-toluenesulfonate. The oxidation can be carried out under the condition selected from the various conditions based on the structure and nature of the compound. Generally, the oxidation is carried out in one or more solvents selected from methanol, water, chloroform, tetrahydrofuran, dioxane, ethanol and methylene chloride in the presence of one or more oxidizing agents selected from sodium periodate, metachloroperbenzoic acid, hydrogen peroxide and OxoneR(monopersulfate compound; DuPont product).
(Method K)
The compound of formula (1) wherein A represents group (k), that is a compound of formula (1k): 
wherein X, R1, R2, R3, R4, R5, m1, m2, m3, n1 and D1 are defined as previously described, can be prepared by a process characterized in that a compound of formula (13): 
wherein X, R3, R4, m1, P and W1 are defined as previously described, is reacted with a compound of formula (44):
xe2x80x83W3Sxe2x80x94(CH2)m2xe2x80x94D1xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(44)
wherein R5, m2, m3, W3 and D1 are defined as previously described, and the resulting compound is then deprotected and oxidized to produce a compound of formula (1ka): 
wherein X, R3, R4, R5, m1, m2, m3, n1 and D1 are defined as previously described.
The reaction of the compound (13) and (44) can be carried out in one or more solvents selected from methanol, ethanol and acetonitrile and optically in the presence of one or more bases selected from sodium hydroxide, sodium ethoxide and sodium methoxide under warming for 1 to 20 hours. The deprotection can be carried out using a conventional method such as hydrolysis in the presence of acid or base. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid and pyridinium-p-toluenesulfonate. The oxidation can be carried out under the condition selected from the various conditions based on the structure and nature of the compound. Generally, the oxidation is carried out in one or more solvents selected from methanol, water, chloroform, tetrahydrofuran, dioxane, ethanol and methylene chloride in the presence of one or more oxidizing agents selected from sodium periodate, metachloroperbenzoic acid, hydrogen peroxide and OxoneR(monopersulfate compound; DuPont product).
(Method L)
The compound of formula (1) wherein A represents group (1), that is a compound of formula (11): 
wherein X, R1, R2, R3, R4, R5,m1, m2, m3 and D1 are defined as previously described, can be prepared by, a process characterized in that a compound of formula (45): 
wherein X, R3, R4, m1 and P) are defined as previously described, is reacted with a compound of formula (46):
W1(CH2)m2W2xe2x80x83xe2x80x83(46)
wherein m2, W1 and W2 are defined as previously described, to produce a compound of formula (47): 
wherein X, R3, R4, m1, m2, W2 and P are defined as previously described, the resulting compound of formula (47) is reacted with a compound of formula (14):
D1H2xe2x80x83xe2x80x83(14)
wherein D1 is defined as previously described, to produce a compound of formula (48): 
wherein X, R3, R4, m1, m2, D1 and P are defined as previously described, the resulting compound of formula (48) is reacted with a compound of formula (16a):
W5xe2x80x94(CH2)m3xe2x80x94R5xe2x80x83xe2x80x83(16a)
wherein R5 and m3 are defined as previously described, and W5 represents a leaving group and then deprotected to produce a compound of formula (1la): 
wherein X, R3, R4, R5, m1, m2, m3 and D1 are defined as previously described.
The coupling step of the compound (45) and (46) may be carried out in a solvent. As the preferable solvent, one or more selected from a group consisting of dioxane, methanol, ethanol, diethylether, tetrahydrofuran, dimethylsulfoxide, methylene chloride, dimethylformamide, chloroform, ethyl acetate, acetonitrile and acetone can be used. This reaction may be carried out optionally in the presence of one or more inorganic or organic bases selected from a group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, triethylamine and cesium carbonate. The reaction may be suitably proceeded under the reflux temperature of the solvent used or room temperature, if appropriate, under ice-cooling.
The coupling step of the compound (47) and (14) in a solvent. As the preferable solvent, one or more selected from a group consisting of dioxane, methanol, ethanol, diethylether, tetrahydrofuran, dimethylsulfoxide, methylene chloride, dimethylformamide, chloroform, ethyl acetate, acetonitrile and acetone can be used. This reaction may be carried out optionally in the presence of one or more inorganic or organic bases selected from a group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, triethylamine and cesium carbonate. The reaction may be suitably proceeded under the reflux temperature of the solvent used or room temperature, if appropriate, under ice-cooling.
The coupling step of the compound (48) and (16a) in a solvent. As the preferable solvent, one or more selected from a group consisting of dioxane, methanols ethanol, diethylether, tetrahydrofuran, dimethylsulfoxide. methylene chloride, dimethylformamide, chloroform, ethyl acetate, acetonitrile and acetone can be used. This reaction may be carried out optionally in the presence of one or more inorganic or organic bases selected from a group consisting of potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, triethylamine and cesium carbonate. The reaction may be suitably proceeded under the reflux temperature of the solvent used or room temperature, if appropriate, under ice-cooling and then deprotected to produce the compound of formula (1la). This reaction can be carried out in one or more solvents selected from a group consisting of acetone, toluene, dimethylformamide, acetonitrile, dimethylsulfoxide and methylene chloride, optionally in the presence of a base such as potassium carbonate, triethylamine, sodium ethoxide, etc. The deprotection reaction may be carried out according to a conventional method such as hydrolysis in the presence of acid or base, reduction, etc. Preferably, the deprotection is achieved in the presence of one or more hydrolyzing agents selected from a group consisting of borontribromide, hydrochloric acid, hydrobromic acid, hydrofluoric acid, pyridinium-p-toluenesulfonate and sulfuric acid, or in the presence of one or more reducing agents selected from a group consisting of Pd(OH)2/C under hydrogen, Pd/C and diisobutylaluminum hydride(DIBAL). This reaction can be carried out under a low temperature to warming, preferably carried out by starting at a low temperature of xe2x88x9278xc2x0 C. and then warming to room temperature. While, the compound of formula (1aa) thus produced may be further oxidized using metachloroperbenzoic acid(mCPBA) in a solvent such as chloroform.
The desired compounds obtained in each processes may be separated and purified using the conventional methods such as column chromatography, recrystallization, etc.
The above processes I to V according to the present invention will be more specifically explained through the following examples.
As stated above, the compound of formula (1) prepared according to the process of the present invention as mentioned above has a good anti-estrogenic activity and, therefore, can be used for the treatment of estrogen-related diseases including anovular infertility, breast cancer, endometrial cancer, uterine cancer, ovarian cancer, endometriosis, endometrial fibroma, benign prostate hypertrophy, premature, menstrual disorder, etc.
Therefore, the present invention relates to an anti-estrogenic pharmaceutical composition containing the compound of formula (1) as an active component.
When the anti-estrogenic pharmaceutical composition containing the compound of the present invention as an active component is used for clinical purpose, it can be formulated into a conventional preparation in the pharmaceutical field, for example, preparation for oral administration such as tablet, capsule, troche, solution, suspension, etc., or injectable preparation such as injectable solution or suspension, ready-to-use injectable dry powder which can be reconstituted with distilled water for injection when it is injected, etc., by combining with a carrier conventionally used in the pharmaceutical field.
Suitable carrier which can be used in the composition of the present invention includes those conventionally used in the pharmaceutical field, for example, binder, lubricant, disintegrant, excipient, solubilizer, dispersing agent, stabilizing agent, suspending agent, coloring agent, perfume, etc. for oral preparation; and preservative, pain alleviating agent, solubilizing agent, stabilizing agent, etc. for injectable preparation. The pharmaceutical preparation thus prepared can be administered orally or parenterally, for example, intravenously, subcutaneously, or intraperitoneally. In addition, in order to prevent the active component from the decomposition with gastric acid, the oral preparation can be administered together with an antacid or in the enteric-coated form of the solid preparation such as tablet.
The dosage of the benzopyran or thiobenzopyran derivative of formula (1) according to the present invention for human being can be suitably determined depending on absorption, inactivation and secretion of the active ingredient in the human body, age, sex and condition of subject patient, kinds and severity of disease to be treated. It is generally suitable to administer the compound of formula (1) in an amount of 1 to 500 mg, preferably 5 to 200, per day for adult patient.